The most effective and durable therapies for advanced melanoma are immune therapies, both FDA-approved (Interleukin-2 (IL-2); CTLA-4 antibody), and in development (e.g., antibody blockade of PD-1/PD-L1). Each of these induces durable clinical benefit in patient subsets; however, overall clinical response rates remain no higher than 20% for IL-2 and for CTLA-4 antibody, and about 30% in early trials with PD-1 antibody. These therapies are mediated directly or indirectly through T cell activation; thus, they are proof-of-principle for the ability of T cell-directed therapies to control melanoma. T cells act by receptor-mediated recognition of specific peptide antigens in association with MHC molecules. Antitumor T cells arise spontaneously in melanoma patients and likely have a role in immune surveillance and immunoediting, and their presence within tumors is associated with improved survival. However, tumor-infiltrating T cells are typically rendered dysfunctional in the tumor micro-environment by numerous soluble and cell-associated factors, including PD-1/PD-L1. Immunologic control of metastatic melanoma can be obtained by therapy that reverses tumor-associated immune dysfunction. However, current monotherapies are associated with significant toxicity, and each benefits only a minority of patients.
Cancer vaccines can expand T cells that specifically lyse human melanoma cells. As monotherapy, peptide vaccines induce clinical responses in only 3-5% of melanoma patients, but they can induce durable clinical responses in some patients. Importantly, they may synergize with other immune therapies to improve clinical benefit when administered as part of combination immunotherapy. For example, clinical outcome of IL-2 therapy was improved significantly by co-administration with a melanoma peptide vaccine. The vaccine used in that regimen incorporated only one short peptide (IMDQVPFSV, gp100209-2M), restricted by HLA-A2, and it was administered in incomplete Freund's adjuvant (IFA). IFA is not optimal for inducing Th1/Tc1 T cell responses, and it may negatively impact T cell persistence and homing to tumor, especially when administered with short peptides. Optimization of peptide vaccines is likely to increase the therapeutic effect of this and other combination therapies. Also, with recent FDA approval of a defined antigen vaccine for prostate cancer, there is support for continued optimization of cancer vaccines. Current melanoma vaccines are not optimized: both the antigens and the adjuvants may be improved. Short peptides can be presented by non-professional antigen-presenting cells (APC) at the vaccine site and may contribute to tolerance or anergy. However, long (30-mer) peptides require processing by dendritic cells and are presented only by professional APC. They offer substantial promise as improved antigens. A long peptide vaccine against HPV has induced dramatic regressions of vulvar neoplasia.
Long Peptides:
Short peptides may bind directly to MHC molecules on cells that are not professional antigen-presenting cells (APC), thereby potentially inducing tolerance or anergy. Instead, long peptides have a tertiary structure that protects from exopeptidase-mediated degradation, and long peptides must be internalized by professional APC and processed for presentation (e.g. CD11c+ DC). Recent work with long (30-mer) peptides that encompass short minimal epitopes suggests that these longer peptides may be more effective immunogens than the minimal peptides. The extra length contributes to a tertiary structure that may protect from peptidases, and they are too long to be presented directly on MHC; so processing is required. This further ensures that the peptides are presented just by professional antigen-presenting cells (APC). A vaccine using long peptides for squamous vulvar neoplasia has induced high rates of clinical regressions, supporting clinical activity of long peptide vaccines. Vaccination with 4 long peptides from NY-ESO-1 in ovarian cancer has demonstrated safety in humans and has demonstrated immunogenicity, including the ability to induce CD8+, CD4+, and antibody responses to the peptide NY-ESO-179-108 (Sabbatini et al., 2012, Clin. Cancer Res. 18:6497). Unlike short peptides, long peptides induce memory CD8+ T cell responses that are boosted dramatically on repeat vaccination in mice, and induce substantially improved tumor control than vaccination with short peptides. Induction of helper T cells reactive to epitopes within the long peptide have been implicated as necessary for long-term T cell memory. Using the long peptides in LPV7 as a vaccine promises to induce a broad and more durable adaptive immune responses against multiple antigens.
CD4 T Cell Induction, to Activation of CD40:
The effects of adjuvants are supported by concurrent stimulation of CD40, which is most naturally effected by expression of CD40L on activated CD4 T cells at the site of vaccination and in draining nodes. An effective way to ligate CD40 specifically on dendritic cells (DC) in the vaccine-site microenvironment (VSME) and in vaccine-draining lymph nodes (VDLN) is to take advantage of physiologic systems where activation of CD4+ cells in the VSME and VDLN will upregulate CD40L on those cells. CD40L+ CD4 cells in turn license professional APC (DC) in tissues where antigen is presented. The peptides in the LPV7 mixture contain immunogenic epitopes for CD4+ T cells. This strategy can be expected to induce CD40L expression and CD40 activation, which can then synergize with activation of TLR.
Human Experience with Long Peptides in Cancer Vaccines:
A human clinical study of vaccination with 4 long peptides from NY-ESO-1 (residues 79-108, 100-129, 121-150, 142-173), has been performed by Dr. Sacha Gnjatic in 21 patients with high-risk ovarian cancer patients (Sabbatini et al., 2012, Clin. Cancer Res. 18:6497). NY-ESO-1 is a cancer-testis antigen. Vaccines were administered subcutaneously (SQ) every 3 weeks alone (n=3), combined with Montanide ISA-51 (IFA, n=9), or combined with IFA+poly-ICLC (n=9). The vaccines were well tolerated. For peptides+IFA, injection site reactions were frequent but self-limited (grade I-II); systemic effects included grade I fatigue and headache. The addition of poly-ICLC led to more intense injection site reactions in some patients. Two grade 3 toxicities were recorded: pneumonia not related to vaccine, and neutropenia possibly related. The long peptides induced all three arms of the adaptive immune response. PolyICLC improved induction and magnitude of antibody (Ab) responses, including responses to multiple epitopes within peptide NY-ESO-179-108, in most patients. CD4 T cells were consistently induced in the large majority of patients vaccinated with IFA or IFA+Poly-ICLC. CD8 T cell responses were observed in most patients, with greater consistency, magnitude, and breadth when poly-ICLC was added. T cell responses were typically polyfunctional and polyclonal, with responses to multiple epitopes within NY-ESO-179-108. Multiple T cell epitopes have been defined within the NY-ESO-179-108 sequence (Table 1). Responses were observed to many of the defined antigens contained in this sequence, as well as to others, in the context of rarer HLA class I and class II alleles.
There is a long felt need in the art for compositions and methods useful for treating and preventing cancer. The present invention satisfies these needs.